Investigation and Modulation of the Mu-Opioid Mechanism in Chronic TMD (in vivo)

Mu-阿片类药物机制在慢性 TMD 中的研究和调节（体内）

• 批准号: 9323372
• 负责人: ALEXANDRE DASILVA
• 金额: $ 43.81万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323372
• 关键词: Absence of pain sensation; Address; Affective; Analgesics; Area; Binding; Brain; Chronic; Clinical; Cognitive; Contralateral; Data; Disease; Electrodes; Evolution; Functional disorder; Goals; High Prevalence; Investigation; Joints; Larrea; Magnetic Resonance Imaging; Measures; Mediating; Methods; Molecular; Motor Cortex; National Institute of Dental and Craniofacial Research; Nature; Neuronal Plasticity; Operative Surgical Procedures; Opioid; Opioid Receptor; Pain; Pain Disorder; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Procedures; Prosencephalon; Questionnaires; Regulation; Reporting; Research; Research Personnel; Scanning; Sensory; Solid; Specificity; Stress; Structure; Symptoms; System; Temporomandibular Joint Disorders; Temporomandibular joint disorder pain; Testing; Thalamic structure; Trigeminal Pain; United States National Institutes of Health; base; carfentanil; central pain; conventional therapy; electric field; experience; follow-up; mu opioid receptors; neuromechanism; neuroregulation; neurotransmission; novel; public health relevance; radiotracer; tool; transmission process

 DESCRIPTION (provided by applicant) Approximately 10% of TMD patients will not experience an improvement of their symptoms and around 75% of patients who fail to respond to conservative treatments are also not suitable for TM joint surgery. Initial studies from our NIH NIDCR R56 project using positron emission tomography (PET) with [11C] Carfentanil, a selective radiotracer for μ-opioid receptor (μOR), have demonstrated that there is a decrease in thalamic µOR availability (non-displaceable binding potential BPND) in the brains of TMD patients during masseteric pain compared to healthy controls. μ-opioid neurotransmission is arguably one of the mechanisms most centrally involved in pain regulation and experience. Moreover, the thalamus is the major relay structure in the forebrain for (non)-noxious inputs, which will be distributed subsequently to multiple cortical areas for discriminative, cognitive and affective processing. MRI-based reports have found that those findings co-localize with neuroplastic changes in trigeminal pain patients. Conventional therapies are unable to selectively target the thalamus and associated regions, and there is a paucity of data on how to reverse neuroplastic molecular mechanisms when available medications fail. Interestingly, several studies with motor cortex stimulation (MCS) have shown that epidural electrodes in the primary motor cortex (M1) are effective in providing analgesia in patients with central pain, and that it occurs via indirect modulation of thalamic activity. Evidently, the invasive nature of sucha procedure limits its indication to highly severe pain disorders. New non-invasive neuromodulatory methods for M1, such as transcranial direct current stimulation (tDCS), can now safely modulate the µOR system, providing relatively lasting pain relief in pain patients. Recently, a novel high-definition tDCS (HD-tDCS) montage created by our group was able to reduce exclusively "contralateral" sensory- discrimative clinical pain measures (intensity/area) in TMD patients by targeting precisely the M1 region. Therefore, the main goals of our study are: First, to exploit the μ-opioidergic dysfunction in vivo in TMD patients compared to healthy controls; Second, to determine whether 10 daily sessions of non- invasive and precise M1 HD-tDCS have a modulatory effect on clinical and experimental pain measures in TMD patients; and Third, to investigate whether repetitive active M1 HD-tDCS induces/reverts μOR BPND changes in the thalamus and other pain-related regions, and whether those changes are correlated with TMD pain measures. The studies above represent a change in paradigm in TMD research, as we directly investigate and modulate in vivo one of the most important endogenous analgesic mechanisms in the brain.

 大约10％的TMD患者的描述（由适用提供）不会改善其症状，而对保守治疗的不反应的患者中约有75％也不适合TM联合手术。 NIH的初步研究 NIDCR R56使用阳性发射断层扫描（PET）和[11C] Carfentanil是一种用于μ-阿普尼受体（μOR）的选择性放射性示例，表明在囊肿患者的大脑中，丘脑的可用性降低了（丘脑可供应量的可用性bpnd），而在囊肿疼痛的情况下，丘脑的可用性降低（非置换性结合潜力bpnd）。 μ阿片神经传递可以说是最集中参与疼痛调节和经验的机制之一。此外，丘脑是（非）不受欢迎的输入的前脑中的主要继电器结构，该结构将在多个皮质区域分配给多个皮质区域，以进行判别，认知和 情感处理。基于MRI的报告发现，这些发现与三叉神经疼痛患者的神经塑性变化共定位。常规疗法无法选择性地靶向丘脑和相关区域，并且在可用的药物失败时，关于如何逆转神经塑性分子机制的数据很少。有趣的是，对运动皮层刺激（MC）的几项研究表明，原发性运动皮层（M1）中的硬膜外电极可有效地提供中心疼痛患者的镇痛作用，并且通过间接调节丘脑活性发生。显然，这种程序的侵入性质将其指示限制为高度严重的疼痛障碍。现在，用于M1的新的非侵入性神经调节方法，例如经颅直流刺激（TDC），现在可以安全地调节μor系统，从而在疼痛患者中相对持久缓解疼痛。最近，我们小组创建的一种新型的高清TDC（HD-TDC）单打能够完全减少“对侧”感觉 - 歧视性临床疼痛度量（强度/区域） TMD患者通过精确靶向M1区域。因此，我们研究的主要目标是：首先，与健康对照组相比，TMD患者的体内体内μ-蛋白质功能障碍；其次，确定10个非侵入性和精确的M1 HD-TDC的每日课程是否对TMD患者的临床和实验性疼痛度量具有调节作用；第三，为了研究重复的活动M1 HD-TDC是否诱导/恢复丘脑和其他与疼痛相关区域的μorbpnd变化，以及这些变化是否与TMD疼痛度量相关。上面的研究代表了TMD研究中范式的变化，因为我们直接研究并调节体内最重要的内源性镇痛机制之一。